In both clinical and experimental heart failure, activation of the sympathetic nervous system is associated with decreased inotropic responsiveness to Beta-agonists. This decline in cardiac Beta-adrenergic pathways contributes to the impaired contractile behavior of the heart and may sustain the syndrome of congestive heart failure. In this proposal, we shall utilize an avian model of spontaneous cardiomyopathy which has structural, hemodynamic and biochemical characteristics similar to the disease in human. Protocols have been devised to explore the nature and functional significance of changes in cardiac adrenergic pathways during the development of spontaneous cardiomyopathy. In particular, the possible association between changes in the organization and properties of the cardiac microtubular components and inotropic responsiveness of the myopathic hearts to Beta-agonists. Specifically, the following issues will be examined: a) the number and physical properties of cardiac Beta-adrenergic receptors and hormone-sensitive adenylate activities; (b) mechanism of isoproterenol-induced desensitization of the cardiac adenylate cyclase; (c) cardiac microtubule assemply-disassembly cycle in the normal and myopathic myocardium; (d) effect of microtubule inhibitors (colchicine, vinblastine) on the development of cardiomyopathy and the cardia Beta-adrenergic pathways; (e) changes in myocardial energetics during the development of spontaneous and induced cardiomyopathy, and (f) the temporal correlation between altered hormone-receptor interaction in the heart and functional changes affecting contractility. It is hoped that the results of these experiments will provide important new insights into the molecular basis of Beta-adrenergic control of cardiac function in the failing myocardium.